A. Field of the Invention
The present invention relates generally to derivatives of belactosin and their synthesis. Certain belactosin derivatives of the present invention are inhibitors of both fatty acid synthase and the proteasome. As such, these derivatives, in certain embodiments, are candidates as anticancer and/or auto-immune therapeutics, antivirals, or antibiotics. The synthesis of these compounds generally comprises a concise, single step formation of a common beta-lactone (2-oxetanone) moiety.
B. Background of the Invention
Belactosin and its derivatives have recently garnered interest in the scientific community due to their potential anti-cancer activities. Initial studies of the belactosins revealed that these molecules could represent good lead compounds for cancer treatment by regulating the ubiquitin-proteasome pathways. Mizukami et al., 1997; Asai et al., 2004. The ubiquitin-proteasome pathway generates peptide products with a narrow length distribution centered around 8-12 mers, a size suitable for binding to MHC class 1 molecules. Groll et al., 2005; Michalek et al., 1993. This process allows CD8+ T lymphocytes to identify and eliminate cells that are synthesizing abnormal or “foreign” proteins, as may arise through mutations or infection by viruses. Cresswell et al., 1999. The 20S proteasome is the central component of this degradation system. Kumaraswamy et al., 2006. Certain belactosins have been shown to exhibit behavior similar to that of lactacystin, an inhibitor of the 20S proteasome. Kumaraswamy et al., 2006. Proteasome inhibitors represent a novel anticancer therapy. Adams et al., 2000; Murray et al., 2000; Adams et al., 1999; Adams et al., 2002a; Adams et al., 2002b. It has been shown that belactosins A and C arrest cell-cycle progression at the G2/M phase. Asai et al., 2000. Belactosin and its derivatives feature a beta-lactone ring, and this moiety is pivotal for bioactivity. Kumaraswamy et al., 2006. Thus, synthetic derivatives of belactosin featuring this moiety are potential therapeutic targets of the proteasome.

Orlistat, a drug approved for treating obesity, also features such a beta-lactone ring moiety. Purohit et al., 2006; Kridel et al., 2004; Knowles et al., 2004. This drug has recently been shown to be a potent inhibitor of human fatty acid synthase (FAS); further, this natural product derivative is cytotoxic and cytostatic to tumor cells in vitro and can inhibit tumor growth in vivo. Kridel et al., 2004; Knowles et al., 2004. FAS is responsible for the cellular synthesis of palmitate and is attracting great interest as a drug target in oncology because it is up-regulated in most solid tumors, including those of the breast, prostate and ovary. Purohit et al., 2006; Alo et al., 1996; Swinnen et al., 2002; Rossi et al., 2003; Pizer et al., 1996a; Pizer et al., 1996b; Pizer et al., 2000; Pizer et al., 2001; Gansler et al., 1997. Furthermore, a number of studies show that a pharmacologic blockade of FAS can be cytostatic and cytotoxic to tumor cells. Kuhajda et al., 2000; Kuhajda et al., 1994; Pizer et al., 1998; Funabashi et al. 1989; Pizer et al., 2000. However, orlistat has poor solubility and poor bioavailability, so there is a need to develop new beta-lactones that overcome these problems and that can be deployed as potential antitumor drugs. In addition, simplified derivatives that are readily prepared would also ultimately be attractive from the standpoint of process development.
Previous syntheses of belactosin and derivatives have relied on multi-step syntheses of the beta-lactone moiety involving, for example, aldol chemistry followed by a subsequent lactonization step. In addition, syntheses to date have focused on synthesis of appropriate beta-lactones followed by coupling to a dipeptide. To date, there have been three known reports of syntheses of belactosin and derivatives. Armstrong and Scutt, 2004; Larionov and de Meijere, 2004; Kumaraswamy et al., 2006. Improved methods of preparing belactosin and derivatives are needed, such as methods involving fewer synthetic steps.